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Louisiana State University Health Sciences Center New Orleans, Louisiana
Whether an infection occurs after an infectious challenge rests on a balance between the virulence of the pathogen and the ability of the host to mount an adequate defensive response. In some cases (SARS, for example), a rapidly proliferating and virulent pathogen overwhelms otherwise effective pulmonary host defenses. In other cases, pulmonary host defenses may be undermined by disease or immunosuppressive therapies such that normally noninfectious pathogens can cause a lethal pneumonia. This part of the Symposium will review how disease processes or therapies may interfere with host defense against pulmonary infection and how these breaks in host defense may be repaired. It is our belief that a better understanding of how pulmonary host defenses operate and are disrupted by disease will lead to new strategies to augment host defense in addition to what is now provided by vaccines. In the current clinical environment, where pathogens are becoming increasingly resistant to antibiotics, such immunomodulatory strategies will likely assume a larger role in the prevention and treatment of pulmonary infections.
HIV Infection
J. M. Beck
HIV infection is well recognized to impair pulmonary host defense, largely due to depletion of CD4+ T-lymphocytes, critical cells for the initiation of adaptive immune responses. Less well understood is the fact that the lung is a major reservoir of HIV, mainly resident in alveolar macrophages, and that the pulmonary HIV load may evolve differently and express resistance to antivirals differently than HIV in extrapulmonary tissues. During HIV infection, lavaged CD4+ T-lymphocyte numbers decline, while CD8+ T-lymphocyte numbers increase; late in HIV infection, both CD4+ and CD8+ T-lymphocyte numbers are depressed. In addition to decreases in lymphocyte number, lymphocytes from HIV-infected persons have functional deficits, showing impaired proliferation and cytokine release in response to microbial stimuli. Alveolar macrophages also show functional deficits, and many of these may relate to specific HIV-associated pathogens, such as Pneumocystis jirovecii. Little work has been down on functional deficits in pulmonary neutrophils during HIV infection.
Alcohol, Immunosuppression, and the Lung
K. I. Happel, S. Nelson
Although alcoholics have long been recognized to have increased risk for pneumonia due to aspiration, research supports more subtle functional defects in host defense associated with alcohol abuse. An emerging body of data suggests that alcohol disrupts the orchestrated cytokine response to inflammation as well as communication between the innate and adaptive immune systems. Cytokines that are particularly disrupted by alcohol include tumor necrosis factor, chemokines for neutrophils, IL-17, IFN-
, granulocyte–colony-stimulating factor, and the antiinflammatory cytokine IL-10.
Aging
K. C. Meyer
Pneumonia is the leading cause of death due to infection in the elderly. Age-related changes in lung function (particularly with COPD) may interfere with clearance of an infectious challenge. Aging is associated with decreased toll-like receptor expression in alveolar macrophages and impaired release of proinflammatory cytokines. It also appears that age causes a "remodeling" of the adaptive immune system in which naive T-cells decline and there is compromised ability to respond to new antigens. Defects in humoral immunity and in the phagocytic capacity of neutrophils have also been identified.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia
R. G. Wunderink
Only a third of ventilated patients develops pneumonia. It may well be that this subset of patients has impaired host defenses beyond that associated with intubation and critical illness. Clinical data support an initial phase of "immunoparalysis" in critical illness that may predispose to infection. This can be reflected in suboptimal expression of HLA-DR determinants on peripheral blood monocytes and increased serum concentrations of IL-10. Alternatively, there may be congenital defects in host defense that lead to nosocomial pneumonia in a subset of patients. Possibilities include genetic polymorphisms in TLR4 expression as well as in genes for a variety of inflammatory cytokines. The ability to identify specific markers of immunosuppression may stimulate trials of immunomodulatory therapy. Pilot data with IFN- are discussed.
Cancer Chemotherapy
L. Joos, M. Tamm
Treatment with cancer chemotherapeutic agents impairs host defense against infection by inducing neutropenia as well as by altering mucosal barriers in the respiratory and gastrointestinal tracts. The underlying malignancy may also contribute to immunosuppression, as for example through T- and B-cell defects associated with lymphomas.
Transplant-related Immunosuppression
M. D. Duncan, D. S. Wilkes
Solid organ or hematopoietic cell transplantation requires the use of multiple immunosuppressive drugs to prevent graft rejection. All of these immunosuppressants can impair host defense and raise the risk for opportunistic pulmonary infection. Mechanisms of action of specific immunosuppressants are reviewed. In the current era of prophylaxis and antibiotic resistance, the timing of specific infections after transplant is less predictable. A modified timeline for transplant-related infection is presented.
Immunosuppression Related to Collagen-Vascular Disease or Its Treatment
C. Dukes Hamilton
Although collagen-vascular diseases may alter host defenses directly, immunosuppression is more commonly the result of therapy. Among therapies for collagen-vascular disease, antibodies to tumor necrosis factor (TNF) carry a particular risk of infection. TNF is critical to maintenance of granulomas. As a result, treatment with anti-TNF antibodies is associated with increased risk of pulmonary and extrapulmonary tuberculosis, as well as histoplasmosis, aspergillosis, cryptococcosis, and listeriosis.
FOOTNOTES
Conflict of Interest Statement: J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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